First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Phase I clinical study of oral olaparib in pediatric patients with refractory solid tumors: study protocol.

BACKGROUND: There is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials. METHODS: In this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m2 b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed. DISCUSSION: This study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients. TRIAL REGISTRATION: UMIN-CTR ( UMIN000025521 ); Registered on January 4, 2017.

[Clinical Utility of Comprehensive Genome Profiling Using FoundationOne CDx in Japanese Population(PROFILE-F Study)].

BACKGROUND: FoundationOne CDx is a cancer genome profiling test that has already been approved by the FDA, but its clinical utility in Japanese patients is unknown. In this study, we examined the clinical utility of FoundationOne CDx. METHODS: 46 samples from 43 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne CDx between September 2018-January 2019. RESULTS: The median age of 43 patients was 63 years(ranged 18 to 82 years), and among them 24 were males and 19 females. Major cancer types were hepato-biliary and pancreatic(8 cases)and other digestive organs(8 cases). All 27 cases in which genome cancer board had been completed by January 17, 2019 were analyzable, and the number of detected gene mutations(except VUS)was an average of 4.3(ranged 0 to 14)per case. Of the 27 cases, one or more mutations were found in 26 cases(96%), and in all such 26 cases actionable mutations with candidates for therapeutic agents were found. In 4(15%)of them, the treatment corresponding to the gene mutation was performed. Among the cases in which target disease matched and clinical trials of the drug were being conducted in Japan, only one case participated in the trial. The most common reason for not participating in the trial was disease deterioration and PS reduction (33%). CONCLUSIONS: The FoundationOne CDx test showed that it can detect gene mutations in various cancer types in Japanese patients.

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial).

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.